This is an application for a K23 award for Dr. Theodore Ruel, an assistant professor in pediatric infectious diseases at the University of California, San Francisco, who is establishing himself as an independent investigator in patient-based translational research of pediatric HIV in Africa. This K23 award will provide Dr. Ruel with the support necessary to accomplish the following goals: (1) to gain skills in the biostatistical analyses of longitudinal data; (2) to receive training in the design and operation of international clinical research; (3) to develop collaborations with leading HIV laboratory scientists (3) to perform research investigating factors in disease progression in HIV-infected African children; and (4) to generate data that will form the basis of an R01 application. Dr. Ruel has assembled a mentoring team to be lead by Dr. Diane Havlir, an accomplished international researcher of the pathogenesis and treatment of HIV, and to include four co-mentors: Dr. Edwin Charlebois, a biostatistician and HIV epidemiologist; Dr. Moses Kamya, a clinical researcher of HIV in Africa; Dr. Joseph K. Wong, an HIV molecular virologist; and Dr. Diane Wara, a pediatric HIV immunologist. Africa bears the greatest burden of the HIV epidemic in children worldwide and there is a great need for more information about endemic strains of HIV to guide management strategies. Mounting data from adults suggest that HIV subtype D strains have increased CXCR4 tropism and lead to more rapid disease progression compared to Subtype A, but there has been limited study in children, who have distinct developing immune physiology. Leveraging the resources of a longitudinal cohort of 300 HIV-infected Ugandan children, Dr. Ruel will test the central hypothesis that HIV Subtype D and D-envelope containing recombinant strains of HIV cause accelerated disease progression compared to HIV Subtype A strains in African children, and investigate several theories about the mechanism and predicted consequences. Specifically, he will compare, by HIV subtype, the rates of disease progression (Aim 1), the prevalence and evolution of CXCR4 tropism (Aim 2), and the levels of proviral HIV DNA in naove and memory lymphocytes (Aim 3). He will also begin to investigate the impact of these factors on CD4 recovery following the initiation of therapy (Aim 4). At the completion of this award, Dr. Ruel will be well positioned to develop an R01 application based on novel data about the pathogenesis of non-subtype B strains of HIV in HIV-infected African children. PUBLIC HEALTH RELEVANCE: Africa is host to an estimated 2 million HIV-infected children, yet there is limited knowledge about the non- subtype B strains of HIV that infect them. The data generated from the proposed research will provide new insight into several factors of disease progression in this population. This information has the potential to inform the development of optimal treatment guidelines that can target those at the greatest need for early therapy, while sparing those who can wait the risks of drug toxicity and the development of resistant virus.